Incidence of the JAK2V617F Mutation in Chronic Myeloproliferative Disorders

Yıl 2013, Cilt: 3 Sayı: 2, 101 - 107, 01.06.2013

Ayşe Kevser Demir Memiş Hilmi Atay Engin Kelkitli Yasemin Turgut Kurt Düzgün Özatlı Mehmet Turgut

Öz

Aim: To determine the frequency of JAK2V617F mutation in BCR/ABL negative chronic myeloproliferative disease (CMD) in the Midle Black Sea region of Turkey, and the effects of this mutation on clinical course of the disease. Method: The study was conducted with 52 patients diagnosed to CMD: twenty-eight polycythemia vera, twenty-one essential thrombocythemia, and three primer myelofibrosis. Age, gender, hemoglobin, hematocrit, platelet and leukocyte values were recorded. The presence of hepatomegaly, splenomegaly, hemorrhage and thrombosis were evaluated.JAK2V617F mutation analyzes were evaluated from the peripheral blood granulocytes by Real Time-PCR Melting Curve. Results: The frequency of JAK2V617F mutation in polycythemia vera, essential thrombocythemia, and primer myelofibrosis were 86% (24/28), 48 (10/21) and 33% (1/3), respectively. There was no significant difference between JAK2V617F mutation and CMD onset age (p>0.05). When the patients divided according to the presence of JAK2V617F mutation, there were higher average level of leukocyte, hemoglobin and hematocrit values in patients with the mutation in polycythemia vera and essential thrombocythemia, but the difference was not statistically significant (p>0.05). The incidence of hepatomegaly were higher in JAK2V617F mutation positive polycythemia vera patients (p=0.030). Average platelet count at diagnosis in essential thrombocythemia patients with JAK2V617F mutation was lower, however, this difference was not statistically significant (p=0.397). Conclusion: The discovery of JAK2V617F mutation provided new information about the molecular basis of BCR/ABL negative CMD. The presence of this mutation affects the clinical features of CMD. In our knowledge, the present study is the first to evaluate the frequency of JAK2V617F mutation on CMD patients in our region, and our results are in concordance with the literature. Further studies with large cohort will be necessitated to better elucidate the effect of JAK2V617F mutation on CMD and confirm these findings.

Anahtar Kelimeler

JAK2V617F mutation, polycythemia vera, essential thrombocythemia, primer myelofibrosis, chronic myeloproliferative disorders

Kronik Miyeloproliferatif Hastalıklarda JAK2V617F Mutasyon Sıklığı

Öz

Amaç: Orta Karadeniz Bölgesi’nde BCR/ABL negatif kronik miyeloproliferatif hastalık (KMH) tanısıyla takip edilen olguların JAK2V617F mutasyon sıklığı ve bu mutasyonun hastalığın klinik özelliklerine etkisi açısından incelenmesi amaçlanmıştır. Gereç ve Yöntem: Çalışmaya kronik miyeloproliferatif hastalık tanısı konulan 52 olgu (28 polistemia vera, 21 esansiyel trombositoz, 3 primer miyelofibrozis) dahil edildi. Hastaların tanı anındaki yaş, cinsiyet, hemoglobin, hematokrit, trombosit ve lökosit değerleri kaydedildi. Hepatomegali, splenomegali, kanama ve tromboz varlığı değerlendirildi. JAK2V617F mutasyon analizi hastaların periferik kan granülositlerinden Real Time-PCR Melting Curve analizi ile yapıldı. Bulgular: JAK2V617F mutasyon sıklığı polistemia vera, esansiyel trombositoz ve primer miyelofibrozis hastalarında sırası ile %85,7 (24/28), %47,6 (10/21) ve %33,3 (1/3) idi. Tanı yaşı ile JAK2V617F mutasyonu arasında istatistiksel olarak anlamlı ilişki tespit edilmedi (p>0,05). JAK2V617F mutasyonu varlığına göre hastalar incelendiğinde polistemia vera ve esansiyel trombositozlu hastalarda mutasyon olanlarda daha yüksek lökosit, hemoglobin ve hematokrit değerleri ile tromboz görülme oranı elde edilmiş olup, aradaki fark istatistiksel olarak anlamlı değildi (p>0,05). JAK2V617F mutasyonu olan polistemia vera hastalarında hepatomegali daha fazla görülmekte idi (p=0,030). JAK2V617F mutasyonu olan esansiyel trombositoz hastalarında tanı anında trombosit sayısı daha düşüktü, fakat aradaki fark istatistiksel olarak anlamlı değildi (p=0,397). Sonuç: JAK2V617F mutasyonun keşfi ile BCR/ABL negatif KMH’ın moleküler temeline ait bilgiler sunmaktadır. Bu mutasyonun varlığı KMH’ın klinik özelliklerini etkilemektedir. Bu çalışma bölgemizde KMH olgularında JAK2V617F mutasyonu sıklığının değerlendirildiği ilk çalışma olup, bulgularımız literatür verileri ile uyumlu bulunmuştur. JAK2V617F mutasyonunun KMH üzerine etkisinin daha iyi anlaşılabilmesi için büyük olgu sayılarını içeren çalışmalara ihtiyaç vardır.

Anahtar Kelimeler

JAK2V617F mutasyonu, polistemia vera, esansiyel trombositoz, primer miyelofibrozis, kronik miyeloproliferatif hastalıklar

Kaynakça

• Wadleigh M, Tefferi A. Classification and diagnosis of myeloproliferative neoplasms according to the 2008 World Health Organization criteria. Int J Hematol 2010;91:174-9.
• Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nat Rev Cancer 2007;7:673-83.
• Bernard OA, Delhommeau F, Fontenay M, Vainchenker W. [Mutations in TET2 in myeloid cancers]. Med Sci (Paris) 2009;25:785-8.
• Carbuccia N, Murati A, Trouplin V, et al. Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 2009;23:2183-6.
• Constantinescu SN. A new era for small molecule screening: from new targets, such as JAK2 V617F, to complex cellular screens. J Cell Mol Med 2009;13:212-214.
• Yamaoka K, Saharinen P, Pesu M, Holt VE 3rd, Silvennoinen O, O'Shea JJ. The Janus kinases (Jaks). Genome Biol 2004;5:253-8.
• Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. J Biol Chem 2007;282:20059-63.
• Verstovsek S. Therapeutic potential of JAK2 inhibitors. Hematology Am Soc Hematol Educ Program 2009:636-42.
• Kristensen DM, Kalisz M, Nielsen JH. Cytokine signalling in embryonic stem cells. APMIS 2005;113:756-72.
• Mahfouz RA, Hoteit R, Salem Z, et al. JAK2 V617F gene mutation in the laboratory work-up of myeloproliferative disorders: experience of a major referral center in Lebanon. Genet Test Mol Biomarkers 2011;15:263-5.
• Nielsen C, Birgens HS, Nordestgaard BG, Bojesen SE. Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population. Br J Haematol 2013;160:70-9.
• Anand S, Stedham F, Beer P, et al. Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood 2011;118:177-81.
• Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-97.
• Pikman Y, Levine RL. Advances in the molecular characterization of Philadelphia-negative chronic myeloproliferative disorders. Curr Opin Oncol 2007;19:628-34.
• James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-90.
• Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-61.
• Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008;22:14-22.
• Tefferi A. Mutational analysis in BCR-ABLnegative classic myeloproliferative neoplasms: impact on prognosis and therapeutic choices. Leuk Lymphoma 2010;51:576-82.
• Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 2005;106:2162-8.
• Karkucak M, Yakut T, Ozkocaman V, et al. Evaluation of the JAK2-V617F gene mutation in Turkish patients with essential thrombocythemia and polycythemia vera. Mol Biol Rep 2012;39:8663-7.
• Stein BL, Moliterno AR. Primary myelofibrosis and the myeloproliferative neoplasms: the role of individual variation. JAMA 2010;303:2513-8.
• Malak S, Labopin M, Saint-Martin C, et al. Long term follow up of 93 families with myeloproliferative neoplasms: life expectancy and implications of JAK2V617F in the occurrence of complications. Blood Cells Mol Dis. 2012;49:170-6.
• Hitoshi Y, Lin N, Payan DG, Markovtsov V. The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases. Int J Hematol 2010;91:189-200.
• Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ. Therapeutic targeting of Janus kinases. Immunol Rev 2008;223:132-42.
• Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol 2008;19:385-93.
• Wan S, Coveney PV. Regulation of JAK2 Activation by Janus Homology 2: Evidence from Molecular Dynamics Simulations. J Chem Inf Model 2012;52;2992-3000.
• Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280:22788-92.
• Levine RL, Gilliland DG. Myeloproliferative disorders. Blood 2008;112:2190-8.
• Vannucchi AM, Antonioli E, Guglielmelli P, Pardanani A, Tefferi A. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia 2008;22:1299-307.
• Renneville A, Quesnel B, Charpentier A, et al. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia 2006;20:2067-70.
• Schmitt-Graeff AH, Teo SS, Olschewski M, et al. JAK2V617F mutation status identifies subtypes of refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Haematologica 2008;93:34-40.
• Vannucchi AM, Antonioli E, Guglielmelli P, et al. Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F) allele burden. Leukemia 2007;21:1952-9.
• Barosi G, Bergamaschi G, Marchetti M, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis. Blood 2007;110:4030-6.
• Landolfi R, Nicolazzi MA, Porfidia A, Di Gennaro L. Polycythemia vera. Intern Emerg Med 2010;5:375-84.
• Lakey MA, Pardanani A, Hoyer JD, et al. Bone marrow morphologic features in polycythemia vera with JAK2 exon 12 mutations. Am J Clin Pathol 2010;133:942-8.
• Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 2007;110:1092
• Vannucchi AM, Antonioli E, Guglielmelli P, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood 2007;110:840
• Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010;363:1117-27.
• De Stefano V, Rossi E, Za T, et al. JAK2 V617F mutational frequency in essential thrombocythemia associated with splanchnic or cerebral vein thrombosis. Am J Hematol 2011;86:526-8.
• Beer PA, Green AR. Pathogenesis and management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program 2009:621-8.
• Campbell PJ, Scott LM, Buck G, et al. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study. Lancet 2005;366:1945-53.
• Carobbio A, Finazzi G, Antonioli E, et al. JAK2V617F allele burden and thrombosis: a direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol Antonioli E, Guglielmelli P, Pancrazzi A, et al. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia. Leukemia 2005;19:1847-9.
• Toyama K, Karasawa M, Yamane A, et al. JAK2V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets. Br J Haematol 2007;139:64-9.
• Patriarca A, Pompetti F, Malizia R, et al. Is the absence of JAK2 mutation a risk factor for bleeding in essential thrombocythemia? An analysis of 106 patients. Blood Transfus 2010;8:21-7.
• Santos FP, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or postpolycythemia vera/essential thrombocythemia myelofibrosis. Blood 2010;115:1131-6.
• Lieu CH, Wu HS, Hon YC, et al. Prevalence of the JAK2-V617F mutation in Taiwanese patients with chronic myeloproliferative disorders. Intern Med J 2008;38:422-6.
• Levine RL, Belisle C, Wadleigh M, et al. Xinactivation-based clonality analysis and quantitative JAK2V617F assessment reveal a strong association between clonality and JAK2V617F in PV but not ET/MMM, and identifies a subset of JAK2V617F-negative ET and MMM patients with clonal hematopoiesis. Blood 2006;107:4139-41.